There are no previously filed, or currently any co-pending applications, anywhere in the world.
1. Field of the Invention
The present invention relates generally to biocompatible materials for systemic and local delivery of therapeutic agents directly within or upon body tissues and, more particularly, to a semisolid therapeutic delivery system and combination semisolid, multiparticulate therapeutic delivery system for therapeutic agents.
2. Description of the Related Art
Approximately 35,000 new brain tumors are diagnosed in adults annually in the U.S. Central nervous system (CNS) malignancies, specifically malignant gliomas, account for 2.5% of all cancer related deaths. Malignant gliomas are the third leading cause of cancer related deaths of persons between the ages of 15 and 34.
In view of the fact that CNS malignancy research has been limited in comparison to other areas of cancer research, this particular malignancy will almost assuredly rise as one of the leading causes of cancer deaths in the U.S.
Malignant gliomas result in tumor formation within the central nervous system. These tumors rapidly grow and infiltrate normal tissues, which result in enlarged tumors compressing normal brain tissue, and in turn, cause abnormality and usually necrosis within the tumor itself, thus requiring removal of the tumor.
Conventional methods of cancer treatment include surgical removal, radiation and chemotherapy. Surgical removal is the initial treatment of choice. Subsequent radiation therapy operates to effectuate physical damage to malignant cells so as to render them incapable of cell division. Chemotherapy generally involves administering drugs that alter the normal structure, function and replication of DNA. Chemotherapy has generally been of limited utility in malignant gliomas due to the fact that most chemotherapeutic agents have very poor penetration into the central nervous system. As a result, clinicians are forced to dose these agents in an aggressive manner in order to increase the systemic concentration to force the drug into the central nervous system. Such aggressive therapy often results in dose proportional systemic side effects such as depression and impairment of normal bone marrow function, which leaves the patient susceptible to a multitude of infections due to the depletion of normal white blood cells. In addition, these agents are toxic to many organ systems including the liver, kidneys, and lungs.
Consequently, conventional treatment methods with respect to malignant gliomas have resulted in a very dismal long-term prognosis, with a mean 24-month survival of 15-20% of patients. Thus, approximately 85% of patients suffering from a malignant glioma will die within the first two years following diagnosis. This stems from an unusually high rate of tumor recurrence due to incomplete surgical resection. Malignant cells usually infiltrate normal tissue surrounding the primary focus itself and are left behind; hence the need for radiation and chemotherapy following surgical removal of the tumor.
In order to remedy inefficient delivery of chemotherapeutic agents so as to prevent reoccurrence of malignant tumors, pharmaceutical scientists developed the concept of local drug delivery. This concept involves the instillation or application of a drug directly to a sight of action; i.e., the brain. This theoretical strategy led to the development of a drug loaded wafer composed of a biodegradable, polyanhydride polymer, manufactured under the brand name Biodel(copyright) by Guilford Pharmaceuticals Inc., Baltimore, Md. The chemical name for the polymer system is poly[bis(p-carboxyphenoxy)propane: sebacic acid]. The drug-loaded wafers, Gliadel(copyright) Wafers, are of a solid, disc-shaped configuration approximately the size of a dime. Each wafer is approximately 1.4 centimeters in diameter, approximately 1 mm in thickness and weighs approximately 200 milligrams. Each wafer contains approximately 7.7 milligrams of a drug called BCNU, or carmustine. The chemical name for BCNU is 1,3-bis[2-chloroethyl]-1-nitrosourea. Historically, BCNU has been the common drug choice in the treatment of malignant gliomas primarily due to its ability to penetrate into the central nervous system from the systemic circulation in relatively high concentrations compared to other chemotherapeutic agents.
However, there are various problems associated with the implantation of Gliadel(copyright) Wafers. Firstly, due to the rigid nature of the wafer""s configuration, the size and shape of the resection pocket may represent a significant problem and limitation of therapy. The clinically recommended dose of wafers to date has been from 6-8 wafers, which yields approximately between 46.2 and 61.6 milligrams BCNU. However, often in an attempt to retain as much viable brain tissue as possible, neurosurgeons find that the resection pocket contains insufficient void space to implant the entire course of therapy. In addition, in the very common case of an irregularly shaped tumor, the physical constraints may also compromise the therapeutic benefit. Further, in the case of a large tumor, the wafers, once secured in the resection pocket, may leave a considerable portion of the surface area without direct contact to the tissue.
Consequently, the rigid nature of the wafers seriously limits the ability of the system to directly contact all areas of tissue directly adjacent to the implants. The unexposed areas of tissue may contain tumor cells, thus leaving such cells untreated and viable. This results in areas receiving a preferential drug exposure while tissues which are removed from direct contact with the wafer(s) receive either sub-optimal or, conceivably, no therapy.
In addition, after a neurosurgeon has removed the bulk of a tumor and has lined the resection pocket with Gliadel(copyright) Wafers, a large void volume remains. Neurosurgeons pack this void with bio-absorbent materials such as Gelfoam(copyright) (absorbable gelatin sponge) to secure the placement of the disks and to prevent brain tissue from herniating into the resection pocket. Thus the large void volume, which could be used for drug delivery, is inefficiently utilized.
There are also many practical problems associated with the handling of Gliadel(copyright) Wafers. The wafers are extremely fragile and often break into pieces when removed from their protective packaging. The manufacturer recommends that once a wafer has been broken into 3 or more pieces, it must be discarded.
In addition, the wafers must be maintained at a refrigerated temperature of 0xc2x0 C. or colder for stability reasons. If the wafers are left at room temperature for 6 or more hours, they must be discarded.
Furthermore, with respect to economic factors, acquisition costs for 8 wafers is approximately $12,000 to $15,000. Patient cost is significantly higher and given the current lack of strongly significant efficacy data, third party coverage is limited. Thus patient treatment is often prohibitively expensive.
Accordingly, there is a need for a semisolid delivery system and combination semisolid, multiparticulate delivery system for delivery of therapeutic agents systemically and locally to tissues after implantation, deposition or injection. This system efficiently utilizes the entire cavity, excavation, or void volume to increase drug dosages, optimizes the uniform delivery and consistent distribution of therapeutic agents to large, small and irregularly shaped compartments and to allow easy injection, placement or surgical implantation. The development of the multiparticulate and semisolid delivery system fulfills this need.
A search of the prior art did not disclose any patents that read directly on the claims of the instant invention; however, the following references were considered related.
U.S. Pat. No. 6,028,164 issued in the name of Loomis describes cross-linked compositions formed from a water insoluble copolymer having a bio-resorbable region wherein such compositions when placed in contact with an aqueous environment form hydrogels, which are useful as sealants for porous materials and particularly for implantable prostheses.
U.S. Pat. No. 6,051,576 issued in the name of Ashton et al. describes a means for improving pharmaceutical and pharmacological properties of pharmacologically active compounds or prodrugs by conjugating them together to form a co-drug.
U.S. Pat. No. 6,096,338 issued in the name of Lacy et al. describes a delivery system for hydrophobic drugs.
U.S. Pat. No. 6,102,887 issued in the name of Altman describes a catheter system for injecting therapeutic agents including large molecules into the body and a method for using the same.
U.S. Pat. No. 6,120,789 issued in the name of Dunn describes a method and composition for forming an implant in-situ within a body using non-polymeric materials, and the use of such implants as medical devices and drug delivery systems.
U.S. Pat. No. 6,153,212 issued in the name of Mao et al. describes biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same.
U.S. Pat. No. 6,228,393 issued in the name of DiCosmo et al. describes drug delivery via therapeutic hydrogels.
U.S. Pat. No. 6,201,072 issued in the name of Rathi et al. describes biodegradable low molecular weight triblock poly(lactide-co-glycolide)polyethylene glycol copolymers having reverse thermal gelation properties.
U.S. Pat. No. 6,201,065 issued in the name of Pathak et al. describes multiblock biodegradable hydrogels for drug delivery and tissue treatment.
U.S. patent application Ser. No. 20010000728 submitted in the name of Sawhney et al. describes compliant tissue sealants.
U.S. patent application Ser. No. 20010000142 submitted in the name of Santos et al. describes methods and compositions for enhancing the bioadhesive properties of polymers using organic excipients.
Consequently, a need has been demonstrated for providing an implantable, depositable and/or injectable biocompatible delivery system for sustained and/or immediate local and/or systemic delivery of drugs and therapeutic agents by the invention.
Therefore, it is an object of the present invention to provide an implantable, depositable, and/or injectable delivery system for immediate, sustained local or systemic delivery of drugs and therapeutic agents.
It is another object of the present invention to provide a biodegradable, biocompatible delivery system for drugs and therapeutic agents.
It is another object of the present invention to provide a delivery system, which can provide for the solubilization, stabilization of lipophilic drug compounds in concentrations necessary for therapeutic benefit over the course of therapy.
It is another object of the present invention to provide a delivery system which is malleable and thus can be delivered and manipulated within an implant site so as to conform and adhere to the contours thereof, as well as completely fill the void volume or excavation space.
It is another object of the present invention to efficiently utilize an entire excavation volume to increase therapeutic dosages, to optimize delivery of therapeutic agents, to administer the delivery system in small and irregularly shaped compartments, to ensure uniform, consistent therapeutic agent distribution, and to allow easy surgical implantation.
It is still another object of the present invention to incorporate biodegradable, biocompatible microspheres into the semisolid.
It is another object of the present invention to utilize an emulsification/solvent-evaporation method, spray drying methods, multiple emulsion methods as well as other methods employed in the art for producing pellets, nonpareils, microspheres, nanoparticles or other multiparticulates whereby a therapeutic agent is deposited within or upon the desired multiparticulate structures.
It is another object of the present invention to provide biodegradable, biocompatible microspheres having a therapeutic agent dispersed therein for incorporation into the semisolid delivery system so as to provide immediate, delayed, sequential, concurrent or sustained delivery of therapeutic agent(s).
Briefly described according to one embodiment of the present invention, a semisolid delivery system and combination semisolid, multiparticulate delivery system for therapeutic agents is comprised of a heterogeneous system which utilizes biocompatible, biodegradable microspheres dispersed in a semisolid, biocompatible, biodegradable semisolid delivery system for injection, placement or implantation within the body so as to facilitate local or systemic release of a therapeutic agent(s) within the body.
The semisolid delivery system is comprised of a biocompatible, biodegradable, viscous semisolid system wherein the preferred embodiment is comprised of a biodegradable hydrogel. Preferably, glyceryl monooleate, hereinafter referred to as GMO, is the intended semisolid delivery system.
The hydrogel system is produced by heating GMO above its melting point and adding a warm aqueous-based buffer, which produces a three-dimensional gelatinous composition of variable viscosity based on water content.
Under changing conditions of temperature and water content, the gel system exhibits several phases, which comprise a broad range of viscosity measures. For the purposes of this disclosure, two morphological phases are considered pertinent at room temperature and physiologic temperature and pH, although the ultimate morphological structure may be altered by active(s) or inactive(s) excipients.
The first morphological phase is a lamellar phase gel consisting of approximately 5%-15% aqueous content and approximately 95%-85% GMO content respectively.
The second morphological phase is a cubic phase gel consisting of approximately 15%-45% aqueous content and 85%-55% GMO content respectively.
According to the preferred embodiment a therapeutic agent, such as BCNU is incorporated into the gel so as to provide a system for delivery thereof.
Depending upon solubility of the chosen therapeutic agent(s) or drug compound(s), for example, whether such compound is lipophilic or hydrophilic, different methods are applied for combining the drug and GMO.
Upon incorporation of BCNU into GMO, the viscosity of the resulting gel decreases slightly depending on drug concentration, thus facilitating easier manipulation thereof when employing a modified large bore delivery apparatus.
It is recognized that alternative semisolids and methods of production exist such that the lipophilic nature of the semisolid can be altered, or in the alternative, the aqueous channels contained within the semisolid can be altered. Thus, various therapeutic agents in varying concentrations may diffuse from the semisolid at differing rates, or be released therefrom over various time/concentration profiles.
Because the semisolid delivery system is malleable, it can be delivered and manipulated in an implant site so as to conform to and adhere to all areas of the resection walls thereof, as well as to completely fill the void volume. The semisolid delivery system ensures intimate tissue contact, thorough distribution and uniform delivery throughout the resection walls of a resection pocket. Ease of delivery and manipulation of the delivery system within resection pockets is facilitated via the modified large bore semisolid delivery apparatus. The modified large bore semisolid delivery apparatus facilitates targeted and controlled placement of the delivery system.
The multiparticulate component is comprised of biodegradable, biocompatible, polymeric or non-polymeric systems utilized to produce solid structures including but not limited to nonpareils, pellets, crystals, agglomerates, microspheres, or nanoparticles.
In one embodiment, the multiparticulate component is comprised of biodegradable poly(lactic-co-glycolide) hereinafter referred to as PLGA. As H2O penetrates the PLGA polymer, the ester bonds thereof are hydrolyzed, and monomers, being water soluble, are removed from the PLGA polymer, thus facilitating release of an entrapped drug from within the PLGA polymer microsphere.
The PLGA polymer microspheres are produced via an emulsification/ solvent-evaporation method, which is extended as a non-limiting example of methods to produce these structures. The emulsification/solvent-evaporation method produces spherical multiparticulates whereby the therapeutic agent is dispersed within the system. Following agitation and removal of non-aqueous solvents by evaporation, and final processing procedures, the microspheres are ready for incorporation into the semisolid delivery system.
The present invention further serves to fill the void volume left following the removal or erosion of pathological or diseased tissues, and in so doing, reduces edema, inflammation and the unwanted loss or migration of body fluid(s).
The use of the present invention allows void volumes to be filled with a biodegradable, biocompatible semisolid system which provides an immediate, delayed, sequential, concurrent and/or sustained, local or systemic delivery of drugs and therapeutic agents. As such, it is envisioned that the delivery system can be utilized to deliver antibiotics used to treat infectious diseases including fungal abscesses and bacterial abscesses. It is further envisioned that the delivery system can be utilized to deliver experimental neuroprotective agents directly to the CNS following trauma or stroke. It is still further envisioned that one embodiment of the delivery system can be formulated and utilized for direct application to body tissues as a hemostatic agent. It is still further envisioned that the delivery system can be formulated and utilized for direct application to body tissues for topical drug delivery of agents to be used for the treatment of surgical wounds, general abrasions, lacerations and decubitus ulcers.